This proposal describes a highly unified, enantioselective strategy to the complex, bioactive marine alkaloids palau'amine, axinellamine, and styloguanidine from a common cyclopentane intermediate bearing either a cyclic urea-hydantoin or bis-cyclic guanidines heterocycles. This strategy is suggestive of one possible biogenesis of these natural products and in order to study the various hypotheses posited in the literature, we propose the synthesis of 15N-labelled putative biosynthetic precursors to be subjected to cell-free acetone preparations from producing marine sponges in collaboration with Prof. Ted Molinski (UCSD). A novel method for imidazolone annulation and amino-imidazoline annulation of alkenes will be further developed useful for heterocycle synthesis beyond the current targets. The synthetic strategies proposed and completed (in the case of gymnodimine and now agelastatins) will be put to work to enable synthesis of appropriate conjugates of these natural products to enable a molecular level understanding of the bioacitivites exhibited by these anticancer agents and also begin to unravel the biosynthesis of higher order pyrrole-2-aminoimidazoIe alkaloids. In the case of gymnodimine, further SAR studies and mice toxicity will establish the potential of this natural product as both a cellular probe and as a public health hazard. The biomechanistic studies are enabled by continued productive collaborations with Prof. Jun Liu (Johns Hopkins).